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Novel compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same

Active Publication Date: 2020-06-04
LEGOCHEM BIOSCIENCES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a novel compound that has high inhibitory activity against the enzyme ATX and simultaneously inhibits the production of LPA. This compound can be used as an effective treatment for various disorders such as cardiovascular disorder, cancer, metabolic disorder, kidney disorder, liver disorder, inflammatory disorder, nervous system disorder, respiratory system disorder, fibrotic disease, ocular disorder, cholestatic and other forms of chronic pruritus, or acute or chronic organ transplant rejection. The compound is represented by the chemical formula 1 and can be in the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt forms.

Problems solved by technology

LPA plays a role in tumor cell proliferation and invasion thereof into neighboring tissue, which can result in metastasization.
That is because ATX is expressed to an increased extent in tumors to exhibit an influence on tumor cell proliferation and invasion into neighboring tissue, which can result in metastases formation.

Method used

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  • Novel compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same
  • Novel compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same
  • Novel compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1-1

[Preparation Example 1-1] Preparation of 5-bromo-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Compound im-1a)

[0225]

[0226]5-Bromo-2-chloropyrimidine (2.0 g, 10.3 mmol), 2-aminoindane (1.6 mL, 12.4 mmol), and N,N-diisopropylethylamine (4.5 mL, 25.8 mmol) were dissolved in ethanol (10 mL) and stirred at 90° C. for 2 hours. Upon the completion of the reaction, the mixture was cooled to room temperature, and the resulting solid was filtered, washed with ethanol (20 mL), and dried to obtain the title compound im-1a as a beige solid (2.2 g, 72%).

[0227]MS m / z: 291 [M+1]+

[0228]1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.40 (s, 2H), 7.81 (d, 1H), 7.22-7.13 (m, 4H), 4.56-4.51 (m, 1H), 3.23 (dd, 2H), 2.88 (dd, 2H)

preparation example 1-2

[Preparation Example 1-2] Preparation of 5-bromo-N-{[3-(trifluoromethoxy)phenyl]methyl}pyrimidin-2-amine (Compound im-1b)

[0229]

[0230]Except that 3-trifluoromethoxy benzylamine is used instead of 2-aminoindane, the reaction was carried out in the same manner as Preparation example 1-1 to obtain the title compound im-1b as a light brown liquid.

[0231]MS m / z: 349 [M+1]+

[0232]1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.39 (s, 2H), 8.11 (t, 1H), 7.44 (t, 1H), 7.33 (d, 1H), 7.25 (s, 1H), 7.22 (d, 1H), 4.52 (d, 2H)

preparation example 1-3

[Preparation Example 1-3] Preparation of 5-bromo-N-[4-(3-chlorophenyl)cyclohex-3-en-1-yl]pyrimidine-2-amine (Compound im-1c)

[0233]

(Step 1) Preparation of tert-butyl N-(4-hydroxycyclohexyl)carbamate (Compound im-1c-a)

[0234]After dissolving (1R,4R)-4-aminocyclohexan-1-ol (15.0 g, 0.13 mol) in methylene chloride (250 mL), di-tert-butyl dicarbonate (25.6 g, 0.12 mol) diluted in methylene chloride (100 mL) and triethylamine (45.4 mL, 0.33 mol) were slowly added dropwise thereto in order under stirring at 0° C., followed by stirring for 14 hours at room temperature. The reaction mixture was diluted with distilled water (300 mL) and stirred for 10 minutes to terminate the reaction, followed by extraction with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound im-1c-a as a pink solid (24.5 g, 97%).

[0235]MS m / z: 216 [M+1]+

[0236]1H NMR (CDCl3, 400 MHz), δ ppm: 4.35 (br, 1...

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Abstract

The present invention relates to novel compounds as autotoxin inhibitors for treatment and prophylaxis of conditions or a disorder caused by autotaxin activation or increased concentration of lysophosphatidic acid, and also a pharmaceutical composition containing the same.The novel compounds of the present invention are autotoxin inhibitors, and by inhibiting the production of lysophosphatidic acid, they are useful for treatment or prophylaxis of cardiovascular disorder, cancer, metabolic disorder, kidney disorder, liver disorder, inflammatory disorder, nervous system disorder, respiratory system disorder, fibrotic disease, ocular disorder, cholestatic and other forms of chronic pruritus, or acute or chronic organ transplant rejection.

Description

TECHNICAL FIELD[0001]The present invention relates to novel compounds as autotoxin inhibitors for treatment and prophylaxis of conditions or a disorder caused by autotaxin activation or increased concentration of lysophosphatidic acid, and also a pharmaceutical composition containing the same.BACKGROUND ART[0002]Autotaxin (hereinbelow, abbreviated as ATX) is an enzyme which is responsible for the increase in lysophosphatidic acid in ascites and plasma, and it is a secretory enzyme important for converting lysophosphatidylchloine (hereinbelow, abbreviated as LPC) into lysophosphatidic acid (hereinbelow, abbreviated as LPA) as a bioactive signaling molecule. ATX is also referred to as an ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D. ATX plays a role in causing pathological conditions including fibrosis, arthritis inflammation, neurodegeneration, neuropathic pain, and cancer.[0003]LPA is a physiologically active lipid having an influence on the migration, p...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D498/10C07D519/00C07D471/10C07D413/14C07D413/12C07D403/14C07D401/14C07D513/04
CPCC07D471/04C07D498/10C07D519/00C07D471/10C07D513/04C07D413/12C07D403/14C07D401/14C07D413/14C07D239/42
Inventor LEE, DAE YONCHAE, SANG EUNJUNG, EUN MIYANG, EUN HYECHOI, YOON JEONGCHUNG, CHUL-WOONGSHIN, JU HYUNKIM, YUN KIKWON, HYUN JINRYU, JEONG HEEBAN, EUN HYEKIM, YONG ZUOH, YEONG SOOCHAE, JEIWOOK
Owner LEGOCHEM BIOSCIENCES INC
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